Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.13593

Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis

Parkinson’s disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction. Increasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions. Recent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development.

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Mitochondrial Dysfunction in Parkinson's Disease: New Mechanistic Insights and Therapeutic Perspectives.

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

https://cyberleninka.org/article/n/130052.pdf

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn(2+) homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society.

The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms

Natalizumab, a humanized monoclonal antibody that binds to the cellular adhesion molecule α4-integrin, prevents leukocytes from crossing the blood–brain barrier. It is effective in multiple sclerosis (MS), but its use is limited by the potential risk of progressive multifocal leukoencephalopathy (PML).

### Case report.

A 61-year-old woman with a 7-year history of relapsing-remitting MS developed PML after treatment with natalizumab for 24 months. Past history included breast cancer 13 years prior, treated with lumpectomy, radiotherapy, and chemotherapy, followed by tamoxifen.

Her MS was initially treated with interferon-β over 5 years, during which time her disease developed a relapsing-remitting course, with 2 significant clinical relapses. Additionally, she developed clinically asymptomatic demyelinating lesions on cerebral MRI. Interferon-β was stopped and monthly methylprednisolone was given for 3 months. Her disease remained refractory to treatment and 2 years ago she was commenced on natalizumab. She underwent 6-monthly clinical and radiologic reviews with MRI. There was mild worsening of lower limb spasticity and ataxia over 2 years but no major relapses. MRI at 6, 12, and 18 months showed no new lesions.

Routine MRI at 24 months after commencement of natalizumab showed a region of juxtacortical white matter fluid-attenuated …

Natalizumab-associated PML identified in the presymptomatic phase using MRI surveillance.

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia

The Medical Journal of Australia ISSN: 0025729X 6 May 2013 198 8 440-442 ©The Medical Journal of Australia 2013 www.mja.com.au Notable Cases form activity. CSF bacterial cult testing and polymerase chain r simplex virus and enterovirus we cal testing was negative. The pat to deteriorate, with a declinin progressive quadriparesis and r tating endotracheal intubation a on Day 12 after admission. The nematode Angiostrongylus cantonensis has spread down the eastern coast of Australia over recent decades. A healthy 21-year-old man developed life-threatening eosinophilic meningoencephalitis following ingestion of a slug in Sydney. We describe the first case of this severity in which the patient survived.

/pdf/angiostrongylus-meningoencephalitis-survival-from-minimally-3ra2ja4bgu.pdf

Angiostrongylus meningoencephalitis: survival from minimally conscious state to rehabilitation.

Aims

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments.



Methods

A PubMed search using the term “hereditary spastic paraplegia” and “hereditary spastic paraparesis” was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period.



Results

A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4GALNT1, DDHD1, C19orf12, GBA2, TECPR2, DDHD2, C12orf65, REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the “HSPome.” Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds.



Conclusion

The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mdc3.12184

Nicholas F. Blair

Papers

The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms

Natalizumab-associated PML identified in the presymptomatic phase using MRI surveillance.

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia

Angiostrongylus meningoencephalitis: survival from minimally conscious state to rehabilitation.

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.